US4356302A - 4H-1,4-Benzothiazine derivatives - Google Patents

4H-1,4-Benzothiazine derivatives Download PDF

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Publication number
US4356302A
US4356302A US06/241,984 US24198481A US4356302A US 4356302 A US4356302 A US 4356302A US 24198481 A US24198481 A US 24198481A US 4356302 A US4356302 A US 4356302A
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US
United States
Prior art keywords
benzothiazin
compound according
parts
pyrido
ylidene
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired - Lifetime
Application number
US06/241,984
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English (en)
Inventor
Robert J. Chorvat
Bipinchandra N. Desai
Suzanne E. Radak
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
GDSEARLE & Co A CORPOF DE
GD Searle LLC
Original Assignee
GD Searle LLC
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by GD Searle LLC filed Critical GD Searle LLC
Assigned to G.D.SEARLE & CO., A CORP.OF DE. reassignment G.D.SEARLE & CO., A CORP.OF DE. ASSIGNMENT OF ASSIGNORS INTEREST. Assignors: CHORVAT ROBERT J., DESAI BIPINCHANDRA N., RADAK SUZANNE E.
Priority to US06/241,984 priority Critical patent/US4356302A/en
Priority to DE19823208285 priority patent/DE3208285A1/de
Priority to FR8203956A priority patent/FR2501210B1/fr
Priority to JP57037138A priority patent/JPS57167994A/ja
Priority to GB8206893A priority patent/GB2094308B/en
Priority to CA000397878A priority patent/CA1180702A/en
Priority to US06/373,329 priority patent/US4399279A/en
Publication of US4356302A publication Critical patent/US4356302A/en
Application granted granted Critical
Priority to GB08412350A priority patent/GB2138423B/en
Priority to CA000465592A priority patent/CA1193600A/en
Assigned to G.D. SEARLE AND CO., 1751 LAKE COOK RD., DEERFIELD, IL 60015 A CORP. OF DE reassignment G.D. SEARLE AND CO., 1751 LAKE COOK RD., DEERFIELD, IL 60015 A CORP. OF DE ASSIGNMENT OF ASSIGNORS INTEREST. Assignors: NUTRASWEET COMPANY, THE
Anticipated expiration legal-status Critical
Expired - Lifetime legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D279/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one sulfur atom as the only ring hetero atoms
    • C07D279/10—1,4-Thiazines; Hydrogenated 1,4-thiazines
    • C07D279/14—1,4-Thiazines; Hydrogenated 1,4-thiazines condensed with carbocyclic rings or ring systems
    • C07D279/16—1,4-Thiazines; Hydrogenated 1,4-thiazines condensed with carbocyclic rings or ring systems condensed with one six-membered ring

Definitions

  • the present invention relates to 4H-1,4 benzothiazine derivatives and novel intermediates used in the preparation thereof. More particularly, this invention provides chemical compounds of the formula ##STR1## wherein R and R' each represent hydrogen or lower alkyl containing 1 to 4 carbon atoms; R2 and R3 represent hydrogen, halogen, nitro, amino, or alkoxy containing 1 to 4 carbon atoms; when R2 is other than alkoxy, R3 represents hydrogen and when R2 is an alkoxy group, R3 is hydrogen or the same alkoxy group; Z represents sulfur, sulfinyl or sulfonyl; Ar is phenyl, mono or di substituted phenyl, wherein the substituents may be halogen, hydroxy, trifluoromethyl, methoxy, cyano or lower alkyl having 1 to 4 carbon atoms; and pharmaceutically acceptable acid addition salts of the compounds of the above formula.
  • R and R' hydrogen is preferred.
  • R and/or R' may represent lower alkyl, methyl, ethyl, 1-methyl ethyl, or propyl (i.e., alkyl containing less than 4 carbon atoms). Positioning of the substituents on the phenyl relative to the point of attachment of the phenyl, or where two are present, to each other is not critical.
  • o-, m-, or p-monosubstituted phenyls of the type described above such as o-fluorophenyl, o-chlorophenyl, m-trifluoromethylphenyl, p-bromophenyl and p-hydroxyphenyl and 2, 4-, 2,6-, and 3,4-disubstituted phenyls of the type described above, such as 2,4-dichlorophenyl, 2,6-dichlorophenyl and 3,4-dichlorophenyl.
  • the preferred substituents of the substituted phenyl representing Ar are halogens.
  • Preferred acid addition salts of this invention are those which are pharmacologically acceptable, that is i.e., relatively non-toxic and effective for the purposes set forth here and below.
  • the final product compounds to which this invention relate are useful because of their valuable pharmacological properties.
  • they are anorectic.
  • the anorectic activity of the instant compounds is evident from results of a test showing a dose responsive decrease in food intake and subsequent weight loss upon administration of the compounds of the present invention. The procedure is as follows:
  • Example 39 Three of the groups were administered the compound in Example 39. Each group was assigned a specific dose. The doses were 5.6, 17.8 and 56.2 milligrams per kilogram of body weight.
  • the compound was suspended in a normal saline vehicle (of which less than 1% of it contained a 50/50 mixture of propylene glycol and "TWEEN”® 80). Concentrations of the compound were adjusted so that each rat received a volume of 2 milliliter per kilograms of body weight.
  • the fourth group received 2 milliliter per kilogram of body weight of the vehicle only. The compound and vehicle preparations were given intraperitoneal one hour before the rats were given access to food.
  • Table 1 shows the results of the tests. A student t test was used for making statistical comparisons, and the p-values are based upon two-tailed comparisons.
  • the compound prepared in accordance with the procedure of Example 39 produced a statistically significant dose responsive decrease in food intake when compared to the normal saline control groups.
  • the drug groups showed a statistically significant (as compared with their previous day's weight) dose responsive weight loss after 24 hours, whereas the normal saline group gained an average of 2.9 grams.
  • the compound produced a decrease in food intake and a subsequent loss in weight.
  • the compounds of this invention are ordinarily combined with one or more adjuvants appropriate to the indicative route of administration. If per os, they may be mixed with lactose, sucrose, starch powder, cellulose esters of alkanoic acids, cellulose alkyl ethers, talc, stearic acid, magnesium stearate, magnesium oxide, sodium and calcium salts of phosphoric and sulfuric acids, gelatin, acacia, sodium alginate, polyvinylpyrrolidone, and/or polyvinyl alchohol, and thus tableted or encapsulated for convenient administration; alternatively, they may be dissolved or suspended in water or a comparably innocuous liquid.
  • Parenteral administration may be effected via sterile fluid and ad mixture with water, polyethylene glycol, propylene glycol, ethanol, corn oil, cottonseed oil, peanut oil, sesame oil, benzyl alcohol, sodium chloride and/or various buffers.
  • Other adjuvants and modes of administration are well and widely known in the pharmaceutical arts; see for example, F. W. Martin et. al., "Remington's Pharmaceutical Sciences,” 14th edition, Merck Publishing Co., Eaton Pa. 1965.
  • R2 when R2 is not an amino group can be prepared as follows: a 2H-1, 4-benzothiazin-3-(4H)-one of the formula ##STR3## wherein R2 is hydrogen, halogen, nitro and/or alkoxy containing 1 to 4 carbon atoms and, when R2 is other than alkoxy, R3 is hydrogen, when R2 is alkoxy, R3 is hydrogen or the same alkoxy, is heated in 1,4-dioxane with diphosphorus pentasulfide to obtain a corresponding thione comprehended by the formula ##STR4##
  • Such a methylthio compound is heated in N,N-dimethylformamide under nitrogen with the sodio derivative of an optionally substituted 2-phenylacetonitrile prepared in situ by contacting the nitrile with sodium hydride, whereby a correspondingly optionally substituted 2-phenyl-2-[2,3-dihydro-4H-1,4-benzothiazin-3-ylidene] acetonitrile is obtained which is comprehended by the formula ##STR6##
  • adducts are converted to the corresponding tricyclic systems by two methods: method A, wherein intermediate compound A is treated with bis (dimethylamino) methoxy methane in DMF at 55 degrees to 60 degrees C. for 3 to 18 hours; method B, wherein the aforementioned adducts represented by intermediate compound A are converted to tricyclic pyrimidones by heating this adduct at 80 to 140 degrees centigrade ##STR10## in DMF from 1 to 6 hours.
  • Such a 2,5 dialkyl-4-phenyl-5H-pyrido [3,4-b][1,4] benzothiazin-3(2H)-one is contacted with ethaneperoxoic acid in acetic acid to obtain a 10-oxide comprehended by the formula ##STR16## and such a 10-oxide or its immediate precursor is heated with ethaneperoxoic acid in acetic acid to obtain a corresponding 10,10-dioxide comprehended by the formula ##STR17##
  • a 4-phenyl-5H-pyrido [3,4-b][1,4] benzothiazin-3(2H)-one of the formula ##STR18## is (1) heated with bromine in a mixture of carbon tetrachaloride and acetic acid to obtain a corresponding 8-bromo compound comprehended by the formula ##STR19## or (2) contacted with a cold mixture of nitric and sulfuric acids to obtain a corresponding 8-nitro 10-oxide comprehende
  • phenylacetonitriles appropriate for Method B may include but should not be limited to p-bromophenylacetonitrile, p-fluorophenylacetonitrile, p-methoxyphenylacetonitrile.
  • a mixture of 12 parts 50% sodium hydride/mineral oil dispersion previously washed with hexane to remove the oil is suspended in 300 ml of DMF under a nitrogen atmosphere and is treated with 32 parts of p-chlorophenylacetonitrile. After the mixture is stirred at room temperature for 15 minutes to 2 hours, 30 parts of 3-methylthio-2H-1,4-benzothiazine from Example 1 is added to the mixture and the reaction mixture stirred at room temperature for one hour.
  • the mixture is neutralized with acetic acid and diluted with one to two volumes of water.
  • the mixture is stirred at room temperature for 30 minutes during which time the product which precipitated from the reaction mixture is filtered and dried to yield (2H-1,4-benzothiazin-3(4H)-ylidene)(4-chlorophenyl)acetonitrile melting at approximately 137°-139°.
  • the yellow material is further triturated with about 500 parts of methanol with heating then cooled, and the solid is collected, washed with ethyl acetate followed by ether and dried.
  • the yellow crystalline solid is recrystallized from aqueous DMF to yield 4-(4-chlorophenyl)-5H-pyrido[3,4-b][1,4] benzothiazin-3(2H)-one which melts above 330°.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Child & Adolescent Psychology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Diabetes (AREA)
  • Hematology (AREA)
  • Obesity (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen- Or Sulfur-Containing Heterocyclic Ring Compounds With Rings Of Six Or More Members (AREA)
  • Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
US06/241,984 1981-03-09 1981-03-09 4H-1,4-Benzothiazine derivatives Expired - Lifetime US4356302A (en)

Priority Applications (9)

Application Number Priority Date Filing Date Title
US06/241,984 US4356302A (en) 1981-03-09 1981-03-09 4H-1,4-Benzothiazine derivatives
DE19823208285 DE3208285A1 (de) 1981-03-09 1982-03-08 4h-1,4-benzothiazinderivate und deren zwischenprodukte
FR8203956A FR2501210B1 (fr) 1981-03-09 1982-03-09 Derives de la 4h-1,4-benzothiazine, leurs utilisations en therapeutique en tant qu'agents anorexiques, leur preparation et produits intermediaires de leur preparation
JP57037138A JPS57167994A (en) 1981-03-09 1982-03-09 Benzothiazine derivative
GB8206893A GB2094308B (en) 1981-03-09 1982-03-09 Azaphenothiazines
CA000397878A CA1180702A (en) 1981-03-09 1982-03-09 4h-1,4-benzothiazine derivatives and intermediates
US06/373,329 US4399279A (en) 1981-03-09 1982-04-30 4H-1,4-Benzothiazine derivatives and intermediates thereto
GB08412350A GB2138423B (en) 1981-03-09 1984-05-15 Intermediates which may be used for the preparation of 4h-1,4-benzothiozine derivatives
CA000465592A CA1193600A (en) 1981-03-09 1984-10-16 4h-1,4-benzothiazine derivatives and intermediates

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
US06/241,984 US4356302A (en) 1981-03-09 1981-03-09 4H-1,4-Benzothiazine derivatives

Related Child Applications (1)

Application Number Title Priority Date Filing Date
US06/373,329 Division US4399279A (en) 1981-03-09 1982-04-30 4H-1,4-Benzothiazine derivatives and intermediates thereto

Publications (1)

Publication Number Publication Date
US4356302A true US4356302A (en) 1982-10-26

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US06/241,984 Expired - Lifetime US4356302A (en) 1981-03-09 1981-03-09 4H-1,4-Benzothiazine derivatives

Country Status (6)

Country Link
US (1) US4356302A (enrdf_load_stackoverflow)
JP (1) JPS57167994A (enrdf_load_stackoverflow)
CA (1) CA1180702A (enrdf_load_stackoverflow)
DE (1) DE3208285A1 (enrdf_load_stackoverflow)
FR (1) FR2501210B1 (enrdf_load_stackoverflow)
GB (2) GB2094308B (enrdf_load_stackoverflow)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4500708A (en) * 1984-04-23 1985-02-19 G. D. Serle & Co. Benzothiazine derivatives

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4223136A (en) * 1979-08-03 1980-09-16 G. D. Searle & Co. 2,3-Dihydro-3-oxo-5H-pyrido[3,4-b][1,4]-benzothiazine-4-carbonitriles

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3118884A (en) * 1959-10-19 1964-01-21 Schering Corp Derivatives of 3-azaphenothiazine and 3-azaphenoxazine
US3196076A (en) * 1961-12-20 1965-07-20 Schering Corp Anti-depressant 10-(3-dimethylaminopropyl)-3-azaphenothiazine

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4223136A (en) * 1979-08-03 1980-09-16 G. D. Searle & Co. 2,3-Dihydro-3-oxo-5H-pyrido[3,4-b][1,4]-benzothiazine-4-carbonitriles

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4500708A (en) * 1984-04-23 1985-02-19 G. D. Serle & Co. Benzothiazine derivatives
EP0159692A3 (en) * 1984-04-23 1987-02-04 G.D. Searle & Co. Annulated 4h-1,4-benzothiazine derivatives

Also Published As

Publication number Publication date
JPH0378399B2 (enrdf_load_stackoverflow) 1991-12-13
GB2094308A (en) 1982-09-15
GB2138423A (en) 1984-10-24
GB2094308B (en) 1985-09-25
FR2501210A1 (fr) 1982-09-10
FR2501210B1 (fr) 1985-10-31
GB8412350D0 (en) 1984-06-20
DE3208285A1 (de) 1982-11-04
CA1180702A (en) 1985-01-08
GB2138423B (en) 1985-09-18
JPS57167994A (en) 1982-10-16

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